PROJECT SUMMARY Endoplasmic reticulum (ER) stress has emerged as an important mediator of disease pathology. Over the last decade, hundreds of studies performed in cell culture and experimental animal models have demonstrated that inhibition of ER stress prevents or reverses numerous chronic diseases, including cardiovascular disease (CVD). Aging is the primary risk factor for cardiovascular disease (CVD). One critical process that links aging to CVD is the development of vascular dysfunction, characterized by endothelial dysfunction and arterial stiffness. Both endothelial dysfunction and arterial stiffness predict cardiovascular events in older individuals. Aging often coincides with obesity, another independent risk factor for CVD. Although vascular function is well characterized in both aging and obesity, it?s currently unclear how these two physiological states interact to modulate vascular function, and whether the combination of aging and obesity has additive or compounding effects on endothelial dysfunction and arterial stiffness. Another important question regarding aging and obesity is whether vascular dysfunction is driven by the same underlying cellular mechanisms in both conditions. Accumulating data in experimental animals, including preliminary results in this application, suggest that ER stress may be an important factor in aging- and obesity-related vascular dysfunction. Published data from our laboratory demonstrate that middle-aged and older obese adults with endothelial dysfunction display evidence of ER stress within biopsied endothelial cells. In light of these data, the overall goal of this proposal is to test the hypothesis that ER stress is associated with human vascular dysfunction in the settings of aging and obesity, and to determine the efficacy of the chemical chaperone tauro-ursodeoxycholic acid (TUDCA), an established inhibitor of ER stress, to reduce endothelial cell ER stress and improve vascular function in these at-risk individuals. Aim 1 will determine the relative contributions of aging and obesity on vascular dysfunction and endothelial ER stress in humans. We hypothesize that aging and obesity will have additive effects on vascular dysfunction and ER stress, and that endothelial ER stress will be correlated with vascular dysfunction in the entire cohort. Aim 2 will determine whether 8 weeks of TUDCA administration improves vascular function and ER stress in older lean and obese humans. Our primary hypothesis is that TUDCA reduces endothelial cell ER stress and improves endothelial function and arterial stiffness in older and/or obese individuals . Our secondary hypothesis is that one of the mechanisms by which inhibition of ER stress via TUDCA will improve vascular function is via a reduction in oxidative stress. Results from this study have the potential to identify a novel, safe, and clinically relevant intervention strategy for the treatment of vascular dysfunction in an aging population at high-risk for the development of CVD.